Azole derivatives and anti-ulcerative composition containing same

ABSTRACT

Compounds of the general formula (I): ##STR1## and pharmaceutically acceptable salts thereof, in which 
     A, B, C and D each represent --CH═ or --N═, with the proviso that at least one of them is --N═; 
     X represents --NH--, --O-- or --S--; 
     Y represents --(CH 2 ) p  -- wherein p is an integer from 0 to 4, --C(CH 3 ) 2  --, --CH 2  CH═CH--, --CH 2  CO--, --CF 2  -- or --CH 2  COCH 2  --; 
     R 1  represents a hydrogen atom, a C 1-4  alkyl group, a halogen atom or a C 1-4  alkoxy group; 
     R 2  represnts a hydrogen atom, a hydroxyl group, a saturated or unsaturated C 1-6  alkyl group, a C 1-6  alkoxy group, a carboxyl group, a saturated or unsaturated C 1-12  alkoxycarbonyl group which may be optionally substituted, a cycloalkoxycarbonyl group, a saturated or unsaturated five- or six-memebered heterocyclic group containing at least one nitrogen atom optionally with one or more nitrogen and/or oxygen atoms, which may be optionally condensed and/or substituted, --CONR 3  R 4 , --NR 3  R 4 , --OCOR 3  or --NHCONHR 3  wherein R 3  and R 4 , which may be the same or different, represent a C 1-6  alkyl group which may be optionally substituted or a cycloalkyl group, and 
     m and n each represent an integrer from 0 to 2. 
     The compounds are useful in treating ulcers.

This application is a division of application Ser. No. 544,671, filed Jun. 27, 1990, now U.S. Pat. No. 5,079,255.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to azole derivatives having an anti-ulcerative activity and anti-ulcerative compositions containing at least one such azole derivative as an active ingredient.

2. Description of the Related Art

Agents which are effective for both inhibiting the secretion of gastric acid and protecting the gastrointestinal mucosa have been demanded as anti-ulcerative compositions.

As agents for inhibiting the secretion of gastric acid, there have been known histamine H₂ -receptor antagonist typically represented by cimetidine. They are, however, ineffective for protecting the gastrointestinal mucosa. Because of their side effects upon the central nervous system, they are also less than satisfactory in their applicability to prevention or treatment of ulcers.

[H⁺ -K⁺ ] ATPase inhibitors typically represented by Omeprazole are strongly effective for inhibiting the secretion of gastric acid, but are known to induce achlorhydria. Another disadvantage of such inhibitors is that they are so unstable to acids that they are likely to be decomposed by gastric acid.

It is thus desired to develop anti-ulcerative agents which not only have a well-balanced effect of both inhibiting the secretion of gastric acid and protecting the gastrointestinal mucosae, but are also efficacious against various ulcers, low toxic and stable to the acid.

We have found that benzothiazole and benzimidazole derivatives have an anti-ulcerative activity (e.g. Japanese Patent Application Ser. No. 293689/88). As a result of further studies, we have now found that some azole derivatives are very efficacious against various, experimentally-induced ulcers, and possess both a strong effect of inhibiting the secretion of gastric acid and an enhanced effect on protecting the gastrointestinal mucosae.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel compounds which not only have a well-balanced effect of inhibiting the secretion of gastric acid and protecting the gastrointestinal mucosae but are also efficacious for preventing or treating ulcers, low toxic and stable to the acid.

Thus, one aspect of the invention provides a novel compound having the formula (I): ##STR2## and pharmaceutically acceptable salts thereof in which

A, B, C and D each represent --CH═ or --N═, with the proviso that at least one of them is --N═;

X represents --NH--, --O-- or --S--;

Y represents --(CH₂)_(p) -- wherein p is an integer from 0 to 4, --C(CH₃)₂ --, --CH₂ CH═CH--, --CH₂ CO--, --CF₂ -- or --CH₂ COCH₂ --;

R₁ represents a hydrogen atom, a C₁₋₄ alkyl group which may be optionally substituted, a halogen atom or a C₁₋₄ alkoxy group which may be optionally substituted;

R² represents a hydrogen atom, a hydroxyl group, a saturated or unsaturated C₁₋₆ alkyl group which may be optionally substituted, C₁₋₆ alkoxy group which may be optionally substituted, a carboxyl group, a saturated or unsaturated C₁₋₁₂ alkoxycarbonyl group which may be ; optionally substituted, a cycloalkoxycarbonyl group, a saturated or unsaturated five- or six-membered heterocyclic group containing at least one nitrogen atom optionally with one or more nitrogen and/or oxygen atoms, which may be optionally condensed and/or substituted, --CONR³ R⁴, --NR³ R⁴, --OCOR³ or --NHCONHR³ wherein R³ and R⁴, which may be the same or different, represents a hydrogen atom, a C₁₋₆ alkyl group which may be optionally substituted or a cycloalkyl group, and

m and n each represent an integer from 0 to 2.

Compounds of formula (I), which have a well-balanced effect of inhibiting the secretion of gastric acid and protecting the gastrointestinal mucosae, are useful in the treatment of ulcerative condition. Accordingly, another aspect of the invention provides a pharmaceutical composition which comprises at least one compound selected from compounds of the general formula (I) and their pharmaceutically acceptable salt.

DETAILED DESCRIPTION Compounds

The compounds according to the present invention are represented by the above-mentioned formula (I).

In the compounds of formula (I), A, B, C and D each represent --CH═ or --N═, with the proviso that at least one of them is --N═. One preferred group of the compound of formula (I) is that in which one or two of A, B, C and D are --N═. If two --N═ exist, then they are preferably found in A and D, B and C or B and D.

In the compounds of formula (I), X represents NH, an oxygen atom or a sulfur atom.

Thus, the compounds of formula (I) according to the present invention have a structure in which a pyridine or azine ring is condensed to an azole ring as basic skeleton or framework, for example, thiazolopyridine, thiazolopyridazine, oxazolopyridine or imidazopyridine skeleton.

In the compounds of formula (I), Y represents --(CH₂)_(p) -- wherein p is an integer from 0 to 4, --C(CH₃)₂ --, --CH₂ CH═CH--, --CH₂ CO--, --CF₂ -- or --CH₂ COCH₂ --.

In the compounds of formula (I), R¹ represents a hydrogen atom; a substituted or unsubstituted C₁₋₄ alkyl group which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxymethyl and ethoxyethyl; a halogen atom such as chlorine and bromine; and a substituted or unsubstituted C₁₋₄ alkoxy group which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and 2,2,2-trifluoroethoxy. One preferred group of compound of formula (I) is that in which R¹ is a chlorine atom at the position B or a trifluoromethyl group at the position C.

In the compounds of formula (I), R² represents (a) a hydrogen atom, (b) a hydroxyl group, (c) a saturated or unsaturated C₁₋₆ alkyl group which may be substituted, (d) a C₁₋₆ alkoxy which may be substituted, (e) a carboxyl group, (f) a saturated or unsaturated C₁₋₁₂ alkoxycarbonyl group which may be substituted, (g) a cycloalkoxycarbonyl group, (h) a saturated or unsaturated five- or six-membered heterocyclic group containing at least one nitrogen atom optionally with one or more nitrogen and/or oxygen atoms, which may be condensed and/or substituted, (i) --CONR³ R⁴ wherein R³ and R⁴, which may be the same or different, each represent a hydrogen atom, a C₁₋₆ alkyl group which may be substituted or a cycloalkyl group, (j) --NR³ R⁴ wherein R³ and R⁴ are each as defined above, (k) --OCOR³ wherein R³ is as defined above, and (1) --NHCONHR³ wherein R³ is as defined above.

The saturated or unsaturated C₁₋₆ alkyl group (c), may be a straight chain or branched chain alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, vinyl, 2-methyl-1-propenyl and 3-methyl-2-butenyl.

The C₁₋₆ alkoxy group (d), of which the alkyl moiety may be a straight chain or branched chain alkyl group, may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy and hexyloxy.

The saturated or unsaturated C₁₋₁₂ alkoxycarbonyl group (f), of which the alkyl moiety may be a straight chain or branched chain alkyl group, may be, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, hexyloxycarbonyl, octoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, l-propenyloxycarbonyl, l-butenyloxycarbonyl, crotyloxycarbonyl, geranyloxycarbonyl and 6,7-epoxygeranyloxycarbonyl.

The cycloalkoxycarbgnyl group (g) may be, for example, cyclopentyloxycarbonyl and cyclohexyloxycarbonyl.

The heterocyclic group (h) is a five- or six-membered ring containing at least one nitrogen atom optionally with one or more nitrogen and/or oxygen atoms, which may be either saturated or unsaturated, may be substituted by a substituent and may be condensed with other ring. The group (h) may be, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-(1methyl)pyrrolidinyl, 3-(1-methyl)pyrrolidinyl, 2-(1ethyl)pyrrolidinyl, 3-(1-ethyl)pyrrolidinyl, 1-piperazinyl, 1-(4-methyl)piperadinyl, 1-piperizinyl, 2(1-methyl)piperidinyl, 3-(1-methyl)piperidinyl, 4-(methyl)piperidinyl, 2,6-dimethyl-1-piperidinyl, 2,2,6,6-tetramethyl-1-piperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-oxazolidinon-5-yl, morpholinyl, 1-methyltetrazol-5-yl, 1-cyclohexyltetrazol-5-yl, 1,3-dioxoisoindol-2-yl and 4-methylimidazol-5-yl.

In the groups (i) --CONR³ R⁴, (j) --NR³ R⁴, (k) --OCOR³ and (1) --NHCONHR³, R³ and R⁴ each represent a hydrogen atom, a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, 2,2,2-trifluoroethyl, or a cycloalkyl group such as cyclohexyl and cyclopentyl groups.

The compounds of formula (I) may exist in the form of their salts resulting from the basicity of the thiazole or pyridine ring moiety which may be found in their skeletons, the acidity of the substituents, and so on. With the use of salts in mind, pharmaceutically acceptable salts are preferred. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid salts such as hydrochlorides, hydrobromides, acetates, succinates and lactates; basic salts with suitable bases such as sodium, potassium, calcium, ammonium, triethylamine and ethanolamine; and amino acid salts with a suitable amino acid such as lysine, arginine and aspartic acid.

It will be appreciated that the compounds of formula (I) have asymmetric carbon or sulfur atoms, and all optical and geometric isomers of compounds of formula (I) are embraced by the invention.

PREPARATION OF THE COMPOUNDS

The compounds of formula (I) according to the present invention are primarily characterized in that the skeleton in which a pyridine or azine ring is condensed to an azole ring has a substituent containing a sulfur atom, a sulfinyl or sulfonyl group, optionally with a substituent being included in the pyridine or azine ring.

The compounds of formula (I) according to the present invention may be synthesized by any method suitable or reasonable in respect of the formation of the above basic skeleton and formation and introduction of the substituents.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be prepared by the general methods outlined hereinafter.

(1) The compounds of the formula (I) wherein n=0 may be prepared by either one of the following processes (A) and (B).

According to a first general process (A), a compound of formula (I) wherein n=0 may be prepared by reacting a compound of the general formula (II): ##STR3## wherein A, B, C, D, X, R¹ and m are as previously defined, with a compound having the general formula (III):

    Z--YR.sup.2                                                (III)

wherein Y and R² are as previously defined, and Z is a halogen atom or a tosyloxy, trifluoromethanesulfonyloxy or mesyloxy group, in the presence of sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or a metal hydride (e.g., sodium hydride, potassium hydride or the like), at a temperature of from -30° to 150° C., preferably 10° to 100° C., for 30 minutes to 24 hours in an inert solvent, such as N,N-dimethylformamide, dioxane, tetrahydrofuran, water or ethanol.

According to another general process (B), a compound of formula (I) wherein n =0, may be prepared by reacting a compound of the general formula (IV): ##STR4##

A, B, C, D, X, R¹ and m are as previously defined and Ha represents a halogen atom such as chlorine, bromine and iodine, with a compound having the general formula (V):

    HS--YR.sup.2                                               (V)

wherein Y and R² are as previously defined, in the presence of sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or a metal hydride (e.g., sodium hydride, potassium hydride or the like), at a reaction temperature of from -30° to 150° C., preferably 10° to 100° C., for 30 minutes to 24 hours in an inert solvent, such as N,N-dimethylformamide, dioxane, tetrahydrofuran, water or ethanol.

(2) The compounds of formula (I) wherein n=1 may be obtained by reacting the compound of the general formula (I) wherein n=0 obtained as above with 1 to 1.2 equivalents of an oxidizing agent in an inert solvent. If the amount of the oxidizing agent is increased to 2 to 3 equivalents in the oxidizing reaction, then it is possible to obtain sulfone compounds having the general formula (I) wherein n=2.

The oxidizing agents used in such oxidizing reactions may include hydrogen peroxide, metachloroperbenzoic acid, tert-butyl hydroperoxide, N-bromosuccinimide, manganese dioxide or the like. The solvents used may be conventional ones, including water, acetic acid, a halogenated alkyl such as methylene chloride, ketones such as acetone or the like. Preferably, the oxidizing reactions may be carried out using hydrogen peroxide in the presence of sodium tungstate in acetic acid or using metachloroperbenzoic acid in methylene chloride.

(3) The compounds of the above general formula (II) may be obtained by reacting a compound of the general formula (VI): ##STR5## wherein A, B, C, D, and R¹ are as previously defined, and M is a halogen atom or an SH group, with carbon disulfide, thiophosgene, potassium methoxanthogenic acid or the like, in an inert solvent such as N,N-dimethylformamide, methanol, ethanol, ethylene glycol monomethyl ether, dioxane or the like), optionally, in the presence of a base (e.g. potassium hydroxide, sodium hydroxide, sodium, potassium carbonate, triethylamine, diisopropylamine or the like).

One example of the process for preparing the compounds of the formula (IV) is known (e.g. Japanese Patent Laid-Open Publication No. 114988/87).

USE OF THE COMPOUNDS/ANTI-ULCERATIVE COMPOSITION

The compounds of formula (I), which have a well-balanced effect of inhibiting the secretion of gastric acid and protecting the gastrointestinal mucosae, are useful in the prevention or treatment of ulcerative conditions.

The compound of formula (I) or salts thereof may be administered as the raw material, but the active ingredient is preferably presented as a pharmaceutical formulation. The compound may be mixed with pharmaceutically acceptable carriers, vehicles and diluents, and may be formulated for oral or parenteral administration. A suitable daily dose of the compound for oral administration to man is 50 to 500 mg. Formulation for parenteral administration by injection may be obtained as an aqueous solution in which a pharmaceutically acceptable, water-soluble salt of the compound is dissolved in water at a concentration of 0.5 to 10% by weight. A suitable dose for administration by injection to man is 0.5 to 10 mg/day.

While the invention is further illustrated by the following Examples, it should be understood that the invention is not limited to the specific examples.

EXAMPLE 1 2-[(n-butoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR6##

Twenty-four (24) g of 2-mercaptothiazolo[5,4-b]pyridine was dissolved in 300 ml of N,N-dimethylformamide, and 43.3 g of potassium carbonate and 23.65 g of chloroacetic acid n-butyl ester were added to the solution, followed by one-hour stirring at room temperature. Seven hundred (700) ml of ethyl acetate was added to the solution, which was then washed with water three times, dehydrated over magnesium sulfate, dried and distilled to remove the solvent to obtain the title compound (39.9 g, 99%).

¹ HNMR(CDCl₃) δ: 0.89 (3H, t), 1.36 (2H, m), 1.63 (2H, m), 4.17 (2H, s), 4.19 (2H, t), 7.35 (1H, dd), 8.04 (1H, d), 8.45 (1H, d).

The compounds having the general formula (I) wherein n=0 were synthesized in similar manners as described in Example 1. The compounds obtained are shown in Examples 2-76.

EXAMPLE 2 2-[(ethoxycarbonylmethyl)thio]thiazolo[4,5-c]pyridine ##STR7##

¹ HNMR(CDCl₃) δ: 1.31 (3H, t), 4.21 (2H, s), 4.27 (2H, ABq), 7.73 (1H, d), 8.45 (1H, dd), 9.13 (1H, s).

EXAMPLE 3 2-[(2-di-isopropylaminoethyl)thio]thiazolo[4,5-c]pyridine ##STR8##

¹ HNMR(CDCl₃) δ: 1.06 (12H, d), 2.88 (2H, t), 3.07 (2H, m), 3.42 (2H, t), 7.70 (1H, dd), 8.42 (1H, d), 9.09 (1H, d).

EXAMPLE 4 2-[(ethoxycarbonylmethyl)thio]-6-trifluoromethylthiazolo[4,5-b]pyridine ##STR9##

¹ HNMR(CDCl₃) δ: 1.31 (3H, t), 4.25 (2H, q), 4.33 (2H, s), 8.37 (1H, s), 8.89 (1H, s).

EXAMPLE 5 2-[(2-di-isopropylamino)ethyl]thio-6-trifluoromethylthiazolo[4,5-b]pyridine ##STR10##

¹ HNMR(CDCl₃) δ: 1.07 (12H, d), 2.91 (2H, t), 3.08 (2H, m), 3.57 (2H, t), 8.31 (1H, s), 8.83 (1H, s).

EXAMPLE 6 2-[(2-(1-methylpyrrolidin-2-yl)ethyl)thio]thiazolo[4,5-c]pyridine ##STR11##

¹ HNMR(CDCl₃) δ: 1.54-1.66 (1H, m), 1.68-1.88 (3H), 1.98-2.08 (1H, m), 2.11-2.30 (3H, m), 2.34 (3H, s), 3.08 (1H, dt), 3.42 (1H, d), 8.44 (1H, d), 9.12 (1H, s).

EXAMPLE 7 2-[(methoxvcarbonylmethyl)thio]thiazolo[5,4-d]pyrimidine ##STR12##

¹ HNMR(CDCl₃) δ: 1.31 (3H, t), 4.20 (2H, s), 4.28 (2H, q), 9.01 (1H, s), 9.10 (1H, s).

EXAMPLE 8 2-[(2-oxopropyl)thio]thiazolo[5,4-b]pyridine ##STR13##

¹ HNMR(CDCl₃) δ: 2.42 (3H, s), 4.25 (2H, s), 7.35 (1H, q), 8.03 (1H, d), 8.45 (1H, d).

EXAMPLE9 2-[(crotyloxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR14##

¹ HNMR{CDCl₃) δ: 1.70 (3H, d), 4.20 (2H, s), 4.61 (2H, d), 5.59 (1H, m), 5.81 (1H, m), 7.35 (1H, q), 8.03 (1H, d), 8.44 (1H, d).

EXAMPLE 10 2-[(geranyloxycarbonylmethyl)thio]thiazolo[5,4-h]pyridine ##STR15##

¹ HNMR(CDCl₃) δ: 1.7 (6H), 2.05 (4H, m), 4.19 (2H, s), 4.70 (2H, d), 5.04 (1H, m), 5.35 (1H, m), 7.33 (1H, q), 8.03 (1H, d), 8.44 (1H, d).

EXAMPLE 11 2-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethylthio-6-trifluoromethylthiazolo[4,5-b]pyridine ##STR16##

¹ HNMR(CDCl₃) δ: 1.11 (12H, s), 1.44 (4H, m), 1.55 (2H, m), 2.91 (2H, m), 3.40 (2H, m), 8.32 (1H, s), 8.85 (1H, s).

EXAMPLE 12 2-[(di-isopropylaminocarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR17##

¹ HNMR(CDCl₃) δ: 1.30 (6H, d), 1.42 (6H, d), 3.52-3.56 (1H, m), 4.07-4.15 (1H, m), 4.44 (2H, t), 7.36 (H, dd), 8.05 (1H, d), 8.45 (1H, d).

EXAMPLE 13 2-[2-(2, 2, 6, 6-tetramethylpiperidin-1-yl)ethyl)thio]thiazolo[5,4-b]pyridine ##STR18##

¹ HNMR(CDCl₃) δ: 1.10 (12H, s), 1.42-1.55 (4H, m), 1.55 (1H, m), 1.67 (1H, m), 2.88 (2H, m), 3.27 (2H, m), 7.33 (1H, dd), 8.01 (1H, d), 8.43 (1H, d).

EXAMPLE 14 2-[(2-ethoxycarbonylethyl)thio]thiazolo[5,4-b]pyridine ##STR19##

¹ HNMR(CDCl₃) δ: 1.28 (3H, t), 2.92 (2H, t), 3.63 (2H, t), 4.20 (2H, q), 7.38 (1H, dd), 8.08 (1H, d), 8.45 (1H, d).

EXAMPLE 15 2-carboxymethylthiothiazolo[5,4-b]pyridine ##STR20##

¹ HNMR(CDCl₃) δ: 4.28 (2H, s), 7.54 (1H, dd), 8.22 (1H, d), 8.50 (1H, d).

EI (m/z): 221 (M-⁻¹).

EXAMPLE 16 2-[(1-ethoxycarbonyl-1-methyl)ethylthio]thiazolo[5,4-b]pyridine ##STR21##

¹ HNMR(CDCl₃) δ: 1.21 (3H, t), 1.78 (6H, s), 4.21 (2H, ABq), 7.36 (1H, dd), 8.08 (1H, dd), 8.48 (1H, dd).

EXAMPLE 17 2-[(allyloxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR22##

¹ HNMR(CDCl₃) δ: 4.22 (2H, s), 4.69 (2H, d), 5.26 (1H, d), 5.37 (1H, d), 5.92 (1H, m), 7.36 (1H, dd), 8.05 (1H, d), 8.46 (1H, d).

EXAMPLE 18 2-[(isopropoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR23##

¹ HNMR(CDCl₃) δ: 1.27 (6H, d), 4.13 (2H, s), 5.10 (1H, m), 7.35 (1H, dd), 8.03 (1H, d), 8.45 (1H, d).

EI (m/z): 268 (M⁺).

EXAMPLE 19 2-[(t-butoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR24##

¹ HNMR(CDCl₃) δ: 1.47 (9H, s), 4.08 (2H, s), 7.35 (1H, dd), 8.03 (1H, d), 8.45 (1H, d).

EI (m/z): 282 (M⁺).

EXAMPLE 20 2-[(3-ethoxycarbonyl-2-oxopropyl)thio]thiazolo[5,4 b]pyridine ##STR25##

¹ HNMR(CDCl₃) δ: 1.29 (3H, t), 3.76 (2H, s), 4.23 (2H, ABq), 4.33 (2H, s), 7.36 (1H, dd), 8.03 (1H, dd), 8.46 (1H, brd).

EXAMPLE 21 2-[(methoxycarbonylmethyl)thio]thiazolo5,4-b]pyridine ##STR26##

¹ HNMR(CDCl₃) δ: 3.80 (3H, s), 4.20 (2H, s), 7.36 (1H, dd), 8.06 (1H, d), 8.45 (1H, d).

EI (m/z): 240 (M⁺).

EXAMPLE 22 2-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethylthio]-1H-imidazo[4,5-b]pyridine ##STR27##

¹ HNMR(CDCl₃) δ: 1.16 (12H, s), 1.65 (6H, s), 3.05 (2H, t), 3.32 (2H, t), 7.15 (1H, dd), 7.87 (1H, d), 8.30 (1H, d).

EI (m/z): 319 (M⁺). EXAMPLE 23 2-[(ethoxycarbonylmethyl)thio]thiazolo[5,4-c]pyridine ##STR28##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 4.21 (2H, s), 4.36 (2H, q), 7.72 (1H, d), 8.57 (1H, d), 9.04 (1H, s).

EXAMPLE 24 2-(2-ethoxycarbonyl-2-oxoethyl)thio]thiazolo-5,4-b]pyridine ##STR29##

¹ HNMR(DMSO-d6) δ: 1.09 (3H, t), 4.05 (2H, m), 4.19 (2H, q), 7.52 (1H, dd), 8.19 (1H, d), 8.50 (1H, d).

EXAMPLE 25 2-[(carbamoylmethyl)thio]thiazolo[5,4-b]pyridine ##STR30##

¹ HNMR(DMSO-d6) δ: 4.18 (2H, s), 7.37 (1H, brs), 7.53 (1H, dd), 7.79 (1H, brs), 8.20 (1H, dd), 8.50 (1H, dd).

EXAMPLE 26 2-[(ethoxycarbonylmethyl)thio]thiazolo[4,5-d]pyridazine ##STR31##

¹ HNMR(CDCl₃) δ: 1.32 (3H, t), 4.25 (2H, s), 4.28 (2H, ABq), 9.60 (1H, s), 9.63 (1H, s).

EXAMPLE 27 2-[(n-propoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR32##

¹ HNMR(CDCl₃) δ: 0.94 (3H, t), 1.68 (2H, m₆), 4.15 (2H, t), 4.18 (2H, s), 7.36 (1H, dd), 8.04 (1H, d), 8.45 (1H, d).

EI (m/z): 268 (M⁺).

EXAMPLE 28 4-chloro-2-[ethoxycarbonylmethyl)thio]thiazolo[4,5-d]pyridazine ##STR33##

¹ HNMR(CDCl₃) δ: 1.33 (3H, t), 4.27 (2H, s), 4.30 (2H, ABq), 9.52 (1H, s).

EXAMPLE 29 2-[(4-(1-cyclohexyltetrazol-5-yl)butyl)thio]thiazolo(5,4-b]pyridine ##STR34##

¹ HNMR(CDCl₃) δ: 1.25-2.10 (14H, m), 2.90 (2H, t), 3.45 (2H, t), 4.10 (1H, m), 7.36 (1H, dd), 8.04 (1H, dd), 8.45 (1H, dd).

EXAMPLE 30 2-[(4-(1-methyltetrazol-5-yl)butyl)thio]thiazolo[5,4-b]pyridine ##STR35##

¹ HNMR(CDCl₃) δ: 1.95-2.10 (4H, m), 2.92 (2H, m), 3.44 (2H, t), 4.00 (3H, s), 7.36 (1H, dd), 8.05 (1H, dd), 8.45 (1H, dd).

EXAMPLE 31 2-[(isobutoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR36##

¹ HNMR(CDCl₃) δ: 0.92 (6H, d), 1.96 (1H, m7), 3.97 (2H, d), 4.19 (2H, s), 7.35 (1H, dd), 8.04 (1H, d), 8.45 (1H, d).

EI (m/z): 282 (M⁺).

EXAMPLE 32 2- 2-[(n-butylcarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR37##

¹ HNMR(CDCl₃) δ: 0.82 (3H, t), 1.26 (2H, m6), 1.44 (2H, m₅), 3.27 (2H, m4), 3.99 (2H, s), 7.08 (1H, s), 7.40 (1H, dd), 8.06 (1H, d), 8.49 (1H, d).

EI (m/z): 281 (M⁺).

EXAMPLE 33 2-methylthiothiazolo[5,4-b]pyridine ##STR38##

¹ HNMR(CDCl₃) δ: 2.80 (3H, s), 7.35 (1H, dd), 8.06 (1H, d), 8.44 (1H, d).

EI (m/z): 182 (M⁺).

EXAMPLE 34 2-[(ethoxycarbonylmethyl)thio]thiazolo[4,5-b]pyridine ##STR39##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 4.25 (2H, q), 4.33 (2H, s), 7.25 (1H, dd), 8.12 (1H, dd), 8.62 (1H, dd).

EXAMPLE 35 2-[(2-di-isopropylaminomethyl)thio]thiazolo4,5-b]pyridine ##STR40##

¹ HNMR(CDCl₃) δ: 1.04 (12H, brs), 2.90 (2H, brs), 3.03 (2H, brs), 3.52 (2H, brs), 7.20 (1H, dd), 8.07 (1H, d), 8.60 (1H, dd).

EXAMPLE 36 2-[(ethoxycarbonylmethyl)thio]thiazolo[4,5-b]pyrazine ##STR41##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 4.25 (2H, q), 4.31 (2H, s), 8.39 (1H, d), 8.56 (1H, brs).

EXAMPLE 37 1.30 (3-ethoxycarbonyl-2-propenyl)thio]thiazolo5,4-b]pyridine ##STR42##

¹ HNMR(CDCl₃) δ: 1.28 (3H, t), 4.14 (2H, dd), 4.19 (2H, q), 6.12 (1H, dt), 7.06 (1H, dt), 7.37 (1H, dd), 8.07 (1H, dd), 8.46 (1H, dd).

EXAMPLE 38 2-[(ethoxycarbonyl)difluoromethyl)thio]thiazolo5,4-b]pyridine ##STR43##

¹ HNMR(CDCl₃) δ: 1.31 (3H, t), 4.37 (2H, q), 7.47 (1H, dd), 8.29 (1H, dd), 8.63 (1H, dd).

EXAMPLE 39 2-[(2-hydroxyethyl)thio]thiazolo[5,4-b]pyridine ##STR44##

¹ HNMR(CDCl₃) δ: 3.56 (2H, t), 4.06 (2H, brt), 7.36 (1H, dd), 8.04 (1H, dd), 8.46 (1H, dd).

EXAMPLE 40 2-[(2-acetoxyethyl)thio]thiazolo[5,4-b]pyridine ##STR45##

¹ HNMR(CDCl₃) δ: 2.08 (3H, s), 3.64 (2H, t), 4.46 (2H, t), 7.36 (1H, dd), 8.06 (1H, dd), 8.45 (1H, dd).

EXAMPLE 41 2-[(2-(1,3-dioxo-isoindol-2-yl)ethyl)thio]thiazolo[5,4-b]pyridine ##STR46##

¹ HNMR(CDCl₃) δ: 3.72 (2H, t), 4.21 (2H, t), 7.30 (1H, dd), 7.69 (2H, dd), 7.83 (2H, dd), 7.94 (1H, dd), 8.41 (1H, dd).

EXAMPLE 42 2-[(isopentoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR47##

¹ HNMR(CDCl₃) δ: 0.89 (6H, d), 1.54 (2H, q), 1.64 (1H, m), 4.18 (2H, s), 4.22 (2H, t), 7.36 (1H, dd), 8.04 (1H, d), 8.45 (1H, d).

EI (m/z): 296 (M)⁺.

EXAMPLE 43 2-[(n-octyl)thio]thiazolo[5,4-b]pyridine ##STR48##

¹ HNMR(CDCl₃) δ: 0.88 (3H, t), 1.27-1.36 (8H, m), 1.48 (2H, m⁵), 1.83 (2H, m⁵), 3.36 (2H, t), 7.34 (1H, dd), 8.04 (1H, d), 8.43 (1H, d).

EI (m/z): 280 (M)⁺.

EXAMPLE 44 2-(isopenthylthio)thiazolo[5,4-b]pyridine ##STR49##

¹ HNMR(CDCl₃) δ: 0.98 (6H, d), 1.69-1.82 (3H, m⁹), 3.37 (2H, t), 7.34 (1H, dd), 8.05 (1H, d), 8.43 (1H, d).

EI (m/z): 238 (M)⁺.

EXAMPLE 45 2-[(n-octoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR50##

¹ HNMR(CDCl₃) δ: 0.87 (3H, t), 1.22-1.28 (10H, m), 1.63 (2H, t), 4.17 (2H, s), 4.17 (2H, t), 7.36 (1H, dd), 8.04 (1H, d), 8.45 (1H, d).

EI (m/z): 338 (M)⁺.

EXAMPLE 46 2-[(cyclopentoxycarbonylmethyl)thio]thiazolo[5,4-b]pyridine ##STR51##

¹ HNMR(CDCl₃) δ: 1.60 (2H, m), 1.71 (4H, m), 1.75 (2H, m), 4.10 (2H, s), 5.25 (1H, m), 7.36 (1H, dd), 8.03 (1H, d), 8.45 (1H, d).

EI (m/z): 294 (M)⁺.

EXAMPLE 47 2-[(2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl)thio]oxazolo[4,5-b]pyridine ##STR52##

¹ HNMR(CDCl₃) δ: 1.11 (l2H, s), 1.43 (4H, t), 1.51-1.54 (2H, m), 2.92 (2H, m⁷), 3.27 (2H, m⁷), 7.17 (1H, dd), 7.68 (1H, d), 8.46 (1H, d).

EI (m/z): 319 (M⁻¹)⁺.

EXAMPLE 48 2-[(2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl)thio]oxazolo[5,4-b]pyridine ##STR53##

¹ HNMR(CDCl₃) δ: 1.10 (12H, s), 1.43 (4H, t), 1.53-1.57 (2H, m), 2.88 (2H, m⁷), 3.23 (2H, m⁷), 7.25 (1H, dd), 7.85 (1H, d), 8.20 (1H, d).

EI (m/z): 320 (M)⁺.

EXAMPLE 49 2-[(methoxycarbonylmethyl)thio]oxazolo[4,5-b]pyridine ##STR54##

¹ HNMR(CDCl₃) δ: 1.31 (3H, t), 4.20 (2H, s), 4.26 (2H, q), 7.20 (1H, dd), 7.73 (1H, d), 8.47 (1H, d).

EI (m/z): 238 (M)⁺.

EXAMPLE 50 2-[(ethoxycarbonylmethyl)thio]oxazolo[5,4-b]pyridine ##STR55##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 4.12 (2H, s), 4.27 (2H, q), 7.28 (1H, dd), 7.88 (1H, d), 8.23 (1H, d).

EI (m/z): 238 (M)⁺.

EXAMPLE 51 2-[(2-di-isopropylaminoethyl)thio]oxazolo[4,5-b]pyridine ##STR56##

¹ HNMR(CDCl₃) δ: 1.07 (12H, d), 2.90 (2H, t), 3.07 (2H, m), 3.43 (2H, t), 7.16 (1H, dd), 7.67 (1H, d), 8.45 (1H, d).

EI (M/z): 280 (M)⁺.

EXAMPLE 52 2-[(2-di-isopropylaminoethyl)thio]oxazolo[5,4-b]pyridine ##STR57##

¹ HNMR(CDCl₃) δ: 1.05 (12H, d), 2.88 (2H, t), 3.06 (2H, m⁷), 3.37 (2H, t), 7.26 (1H, dd), 7.84 (1H, d), 8.19 (1H, d).

EI (m/z): 280 (M)⁺.

EXAMPLE 53 2-[(N-cyclohexylcarbamoylmethyl)thio]thiazolo[5,4-b]pyridine ##STR58##

¹ HNMR(CDCl₃) δ: 1.08-1.86 (10H), 3.78 (1H, m), 3.96 (2H, s), 7.40 (1H, dd), 8.06 (1H, dd), 8.49 (1H, dd).

EI (M/z): 307 (M)⁺.

EXAMPLE 54 2-[(N-methylcarbamoylmethyl)thio]thiazolo[5,4-b]pyridine ##STR59##

¹ HNMR(CDCl₃) δ: 2.84 (3H, d), 4.02 (2H, s), 7.00 (1H, brs), 7.40 (1H, dd), 8.09 (1H, dd), 8.49 (1H, dd).

EI (M/z): 239 (M)⁺.

EXAMPLE 55 2-[((1-cyclohexyltetrazol-5-yl)methyl)thio]thiazolo[5,4-b]pyridine ##STR60##

¹ HNMR(CDCl₃) δ: 1.25-2.15 (10H), 4.55 (1H, m), 4.95 (2H, s), 7.41 (1H, dd), 8.07 (1H, dd), 8.50 (1H, dd).

EI (m/z): 333 (M+1)⁺.

EXAMPLE 56 2-[((1-methyltetrazol-5-yl)methyl)thio]thiazolo[5,4-b]pyridine ##STR61##

¹ HNMR(CDCl₃) δ: 4.24 (3H, s), 4.91 (2H, s), 7.40 (1H, dd), 8.06 (1H, dd), 8.50 (1H, dd).

EI (m/z): 264 (M)⁺.

EXAMPLE 57 2-[(2-ethoxyethyl)thio]thiazolo [5,4-b]pyridine ##STR62##

¹ HNMR(CDCl₃) δ: 1.23 (3H, t), 3.56-3.62 (4H, m), 3.82 (2H, t), 7.35 (1H, dd), 8.06 (1H, d), 8.46 (1H, d).

EI (m/z): 240 (M⁺).

EXAMPLE 58 6-chloro-2-[(2-ethoxyethyl)thio]thiazolo [5,4-b]pyridine ##STR63##

¹ HNMR(CDCl₃) δ: 1.22 (3H, t), 3.52-3.61 (4H, m), 3.80 (2H, t), 8.03 (1H, d), 8.40 (1H, d).

EI (m/z): 274 (M⁺).

EXAMPLE 59 2-[(2-ethoxyethyl)thio]thiazolo[4,5-c]pyridine ##STR64##

¹ HNMR(CDCl₃) δ: 1.22 (3H, t), 3.58 (2H, q), 3.62 (2H, t), 3.82 (2H, t), 7.72 (1H, dd), 8.44 (1H, d), 9.11 (1H, s).

EI (m/z): 240 (M⁺).

EXAMPLE 60 2-[2-ethoxyethyl)thio]1H-imidazo[4,5-b]pyridine ##STR65##

¹ HNMR(CDCl₃) δ: 1.28 (3H, t), 3.53 (2H, t), 3.65 (2H, q), 3.89 (2H, t), 7.18 (1H, dd), 7.92 (1H, d), 8.30 (1H, d).

EI (m/z): 223 (M⁺).

EXAMPLE 61 2-[2(piridin-2-yl)-ethylthio]thiazolo[5,4-b]pyridine ##STR66##

¹ HNMR(CDCl₃) δ: 3.32 (2H, t), 3.81 (2H, t), 3.81 (2H, t), 7.16 (1H, q), 7.22 (1H, d), 7.34 (1H, d), 7.62 (1H, m), 8.06 (1H, q), 8.44 (1H, q), 8.58 (1H, d).

EI (m/z): 273 (M⁺).

EXAMPLE 62 2-[(2-oxazolidin-5-yl)-methylthio]thiazolo[5,4-b]pyridine ##STR67##

¹ HNMR(CDCl₃) δ: 3.54 (1H, dd), 3.64 (1H, dd), 3.82 (1H, t), 3.88 (1H, dd), 5.11 (1H, m), 7.38 (1H, dd), 8.06 (1H, d), 8.47 (1H, d).

EI (m/z): 267 (M⁺).

EXAMPLE 63 2-[(3-methyl-2-butenyl)thio]thiazolo[5,4-b]pyridine ##STR68##

¹ HNMR(CDCl₃) δ: 1.78 (6H, d), 4.02 (2H, d), 5.41 (1H, m), 7.35 (1H, dd), 8.05 (1H, d), 8.44 (1H, d).

EI (m/z): 236 (M⁺).

EXAMPLE 64 2-[(ethoxycarbonylmethyl)thio]thiazole[5,4-b]pyridine ##STR69##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 4.18 (2H, s), 4.26 (2H, q), 7.36 (1H, dd), 8.05 (1H, d), 8.45 (1H, d).

EI (m/z): 254 (M⁺).

EXAMPLE 65 2-[(2-morpholinoethyl)thio]thiazolo [5,4-b]pyridine ##STR70##

¹ HNMR(CDCl₃) δ: 2.55 (4H, t), 2.81 (2H, t), 3.55 (2H, t), 3.72 (4H, t), 7.35 (1H, dd), 8.03 (1H, d), 8.44 (1H, d).

EI (m /z): 281 (M⁺).

EXAMPLE 66 2-[(2-morpholinoethyl)thio]thiazolo[4,5-c]pyridine ##STR71##

¹ HNMR(CDCl₃) δ: 2.53 (4H, t), 2.82 (2H, t), 3.59 (2H, t), 3.72 (4H, t), 7.72 (1H, d), 8.43 (1H, d), 9.12 (1H, s).

EI (m/z): 281 (M⁺).

EXAMPLE 67 2-[(2-N, N-diethylaminoethyl)thio]thiazolo[5,4-b]pyridine ##STR72##

¹ HNMR(CDCl₃) δ: 1.08 (4H, t), 2.63 (4H, q), 2.89 (2H, t), 3.47 (2H, t), 7.34 (1H, dd), 8.03 (1H, d), 8.43 (1H, d).

EI (m/z): 267 (M⁺).

EXAMPLE 68 6-chloro-2-[(2-morpholinoethyl)thio]thiazolo[5,4-b]pyridine ##STR73##

¹ HNMR(CDCl₃) δ: 2.56 (4H, t), 2.82 (2H, t), 3.53 (2H, t), 3.71 (4H, t), 8.00 (1H, d), 8.39 (1H, d).

EI (m/z): 315 (M⁺).

EXAMPLE 69

2-[(2-morpholinoethyl)thio]imidazopyridine ##STR74##

¹ HNMR(CDCl₃) δ: 2.62 (4H, t), 2.90 (2H, t), 3.43 (2H, t), 3.81 (4H, t), 7.17 (1H, dd), 7.90 (1H, d), 8.30 (1H, d).

EI (m/z): 264 (M⁺).

EXAMPLE 70 2-[(2-(1-methylpyrrolidin-2-yl)ethyl)thio]thiazolo[5,4-b]pyridine ##STR75##

¹ HNMR(CDCl₃) δ: 1.55-1.64 (1H, m), 1.67-1.87 (4H, m), 1.97-2.06 (1H, m), 2.10-2.27 (2H, m), 2.33 (3H, d), 3.07 (1H, t), 3.26-3.33 (1H, m), 3.42-3.49 (1H, m), 7.33 (1H, dd), 8.03 (1H, d), 8.42 (1H, d).

EI (m/z): 279 (M⁺).

EXAMPLE 71 2[(2-ureidoethyl)thio]thiazolo[5,4-b]pyridine ##STR76##

¹ HNMR(CDCl₃) δ: 3.39-3.46 (4H, m), 5.54 (2H, s), 6.30 (1H, s), 7.52 (1H, dd), 8.21 (1H, d), 8.49 (1H, d).

EI (m/z): 254 (M⁺).

EXAMPLE 72 2[(1-methylpiperidine-3-yl)methylthio]thiazolo[5,4-b]pyridine ##STR77##

¹ HNMR(CDCl₃) δ: 1.09 (1H, m), 1.56-1.66 (1H, m), 1.68 -1.77 (1H, m), 1.83 (1H, t), 1.89-1.98 (2H, m), 2.06-2.16 (1H, m), 2.27 (3H, d), 2.75 (1H, d), 2.96 (1H, d), 3.33 (2H, dd), 7.34 (1H, dd), 8.04 (1H, d), 8.43 (1H, d).

EI (m/z): 279 (M⁺).

EXAMPLE 73 2-[(1-methylpiperidine-4-yl)thio]thiazolo[5,4-b]pyridine ##STR78##

¹ HNMR(CDCl₃) δ: .189 (2H, m), 2.23-2.27 (4H, m), 2.30 (3H, s), 2.77-2.80 (2H, m), 3.98-4.01 (1H, m), 7.35 (1H, dd), 8.06 (1H, d), 8.44 (1H, d).

EI (m/z): 265 (M⁺).

EXAMPLE 74 2-[(2-di-isopropylaminoethyl)thio]thiazolo[5,4-b]pyridine ##STR79##

¹ HNMR(CDCl₃) δ: 1.04 (6H, d), 1.06 (6H, d), 2.88 (2H, t), 3.06 (2H, m), 3.38 (2H, t), 7.34 (1H, dd), 8.02 (1H, d), 843 (1H, d).

EI (m/z): 295 (M⁺).

EXAMPLE 75 2-[(3-(1-methylpiperazin-4-yl)propyl)thio]thiazolo[5,4-b]pyridine ##STR80##

¹ HNMR(CDCl₃) δ: 2.02 (2H, q), 2.29 (3H, s), 2.50-2.53 (8H, m), 2.51 (2H, t), 3.41 (2H, t), 7.35 (1H, dd), 8.03 (1H, d), 8.44 (1H, d).

EI (m/z): 308 (M⁺).

EXAMPLE 76 (2-di-n-butylaminoethyl)thio]thiazolo[5,4-b]pyridine ##STR81##

¹ HNMR(CDCl₃) δ: 0.93 (6 t), 1.30-1.39 (4H, m), 1.47 (4H, m), 2.53 (4H, m), 2.90 (2H, m), 3.50 (2H, m), 7.34 (1H, dd), 8.02 (1H, d), 8.43 (1H, d).

EI (m/z): 323 (M⁺).

EXAMPLE 77 2-[(ethoxycarbonylmethyl)thio)methyl]thiazolo-[5,4-b]pyridine ##STR82##

2-chloromethyl-thiazolo[5,4-b]pyridine (1.37 g, 7.43 mmol) and triethylamine (827 mg, 8.17 mmol) were dissolved in methylene chloride (10 ml), and ethyl thioglycolate (981 mg, 8.17 mmol) was added dropwise to the solution, while applying ice-cooling and agitation. After the dropwise addition had been completed, the reaction solution was cooled down to room temperature and then stirred for 5 hours. The reaction solution was diluted with chloroform (200 ml), washed with a saturated brine solution (100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (2:1) to obtain the title compound as a colorless oily material, yield: 1.7 g (85%).

¹ HNMR(CDCl₃) δ: 1.27 (3H, t), 3.35 (2H, s), 4.18 (2H, q), 4.26 (2H, s), 7.43 (1H, dd), 8.22 (1H, dd), 8.57 (1H, d).

EXAMPLE 78 2-[(2-di-isopropylaminoethyl)thiomethyl]thiazolo5,4-b]pyridine ##STR83##

The title compound was synthesized in similar manners as described in Example 77.

¹ HNMR(CDCl₃) δ: 0.96 (12H, d), 2.40-2.70 (4H, m), 2.95 (2H, m), 4.14 (2H, s), 7.41 (1H, dd), 8.17 (1H, dd), 8.56 (1H, dd).

EXAMPLE 79 2-[[n-butoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR84##

Dissolved in 50 ml of methylene chloride was 18.5 g of the compound obtained in Example 1, and the solution was cooled down to -10° C. 16.2 g of m-chloroperbenzoic acid (with a 70% purity) was added to the solution, which was in turn stirred at that temperature for 40 minutes. Ethyl acetate (600 ml) was added to the solution, which was then washed once with an aqueous solution of sodium thiosulfate, three times with sodium hydrogencarbonate and once with water, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel column chromatography, and eluting with n-hexane-ethyl acetate (5:3 to 3:1) to obtain the title compound (13.4 g).

¹ HNMR(CDCl₃) δ: 0.88 (3H, t), 1.32 (2H, m), 1.60 (2H, m), 4.14 (1H, d), 4.21 (2H, t), 4.26 (1H, d), 7.55 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

The compounds having the general formula (I) wherein n=1 were synthesized in similar manners as described in Example 79. The compounds obtained are shown in Examples 80-128.

EXAMPLE 80 2-[(ethoxycarbonylmethyl)sulfinyl]thiazolo[4,5-c]pyridine ##STR85##

¹ HNMR(CDCl₃) δ: 1.27 (3H, t), 4.15 (1H, d), 4.27 (1H, d), 4.27 (2H, ABq), 7.99 (1H, d), 8.66 (1H, d), 9.40 (1H, s).

EXAMPLE 81 2-[(ethoxycarbonylmethyl)sulfinyl]-6-trifluoromethylthiazolo[4,5-b]pyridine ##STR86##

¹ HNMR(CDCl₃) δ: 1.29 (3H, t), 4.18 (1H, d), 4.28 (2H, q), 4.37 (1H, d), 8.71 (1H, s), 9.09 (1H, s).

EXAMPLE 82 2-[(ethoxycarbonylmethyl)sulfinyl]thiazolo[5,4-d]pyrimidine ##STR87##

¹ HNMR(CDCl₃) δ: 1.28 (3H, t), 4.17 (1H, d), 4.27 (2H, q), 4.28 (1H, d), 9.23 (1H, s), 9.41 (1H, s).

EXAMPLE 83 2[(2-oxopropyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR88##

¹ HNMR(CDCl₃) δ: 2.39 (3H, s), 4.22 (1H, d), 4.36 (1H, d), 7.55 (1H, dd), 8.31 (1H, d), 8.70 (1H, d).

EXAMPLE 84 2-[(crotyloxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR89##

¹ HNMR(CDCl₃) δ: 1.69 (3H, d), 4.13 (1H, d), 4.25 (1H, d), 4.61 (2H, d), 5.52 (1H, m), 5.78 (1H, m), 7.53 (1H, dd), 8.32 (1H, d), 8.71 (1H, d).

EXAMPLE 85 2[((6,7-epoxy)qeranyloxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR90##

¹ HNMR(CDCl₃) δ: 1.23 (3H, s), 1.30 (3H, s), 1.62 (3H, s), 1.63 (2H, m), 2.12 (2H, m), 2.69 (1H, t), 4.12 (1H, d), 4.26 (1H, d), 4.73 (2H, d), 5.34 (1H, m), 7.54 (1H, dd), 8.30 (1H, d), 8.70 (1H, d).

EXAMPLE 86 2[(di-isopropylaminocarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR91##

¹ HNMR(CDCl₃) δ: 1.24 (6H, d), 1.43 (6H, t), 3.52-3.59 (1H, m), 3.81-3.87 (1H, m), 4.24 (2H, t), 4.36 (1H, d), 7.54 (1H, dd), 8.33 (1H, d), 8.68 (1H, d).

EXAMPLE 87 2[(2-ethoxycarbonylethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR92##

¹ HNMR(CDCl₃) δ: 1.24 (3H, t), 2.63-2.71 (1H, m), 2.96-3.04 (1H, m), 3.42-3.49 (1H, m), 3.64-3.71 (1H, m), 4.13 (2H, q), 7.55 (1H, dd), 8.33 (1H, d), 8.70 (1H, d).

EXAMPLE 88 2[(1-ethoxycarbonyl-1-methyl)ethylsulfinyl]thiazolo5,4-b]pyridine ##STR93##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 1.48 (3H, s), 1.72 (3H, s), 4.28 (1H, ABq)×2, 7.51 (1H, dd), 8.29 (1H, dd), 8.68 (1H, dd).

EXAMPLE 89 2[(allyloxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR94##

¹ HNMR(CDCl₃) δ: 4.23 (2H, ABq), 4.70 (2H, d), 5.25 (1H, dd), 5.32 (1H, dd), 5.86 (1H, m), 7.55 (1H, dd), 8.33 (1H, d), 8.71 (1H, d).

EXAMPLE 90 2[(iso-propoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR95##

¹ HNMR(CDCl₃) δ: 1.25 (6H, d), 4.12 (1H, d), 4.22 (1H, d), 5.11 (1H, m), 7.53 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 285 (M⁺).

EXAMPLE 91 2[(t-butoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR96##

¹ HNMR(CDCl₃) δ: 1.46 (9H, s), 4.06 (1H, d), 4.17 (1H, d), 7.54 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 299 (M⁺¹).

EXAMPLE 92 2-[(3-ethoxycarbonyl-2-oxopropyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR97##

¹ HNMR(CDCl₃) δ: 1.28 (3H, t), 3.66 (2H, ABq), 4.20 (2H, ABq), 4.35 (1H, d), 4.63 (1H, d), 7.55 (1H, dd), 8.33 (1H, dd), 8.71 (1H, dd).

EXAMPLE 93 2-[(methoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR98##

¹ HNMR(CDCl₃) δ: 3.81 (3H, s), 4.15 (1H, d), 4.26 (1H, d), 7.55 (1H, dd), 8.33 (1H, d), 8.71 (1H, d).

EI (m/z): 256 (M⁺).

EXAMPLE 94 2-[(ethoxycarbonylmethyl)sulfinyl]thiazolo[5,4-c]pyridine ##STR99##

¹ HNMR(CDCl₃) δ: 1.27 (3H, t), 4.15 (1H, d), 4.22-4.3 (3H, m), 7.97 (1H, d), 8.76 (1H, d), 9.38 (1H, s).

EXAMPLE 95 2-[(2-ethoxycarbonyl-2-oxoethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR100##

¹ HNMR(CDCL₃) δ: 1.42 (3H, t), 4.40 (1H, d), 4.42 (1H, d), 4.46 (2H, ABq), 7.50 (1H, dd), 8.34 (1H, dd), 8.34 (1H, dd), 8.66 (1H, d).

EXAMPLE 96 2-[(ethoxycarbonylmethyl)sulfinyl]thiazolo[4,5-d]pyridazine ##STR101##

¹ HNMR(CDCl₃) δ: 1.31 and 1.32 (3H, t), 4.20 and 4.22 (2H, s), 4.27 (1H, ABq)×2, 8.59 and 8.64 (1H, d), 8.81 and 8.86 (1H, brs).

EXAMPLE 97 2-[(n-propoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR102##

¹ HNMR(CDCl₃) δ: 0.91 (3H, t), 1.65 (2H, m₅), 4.14 (1H, d), 4.17 (2H, t), 4.25 (1H, d), 7.54 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 285 (M⁺).

EXAMPLE 98 4-chloro-2-(ethoxycarbonylmethyl)sulfinyl]thiazolo[4,5-d]pyridazine ##STR103##

¹ HNMR(CDCl₃) δ: 1.30 (3H, t), 4.19-4.37 (4H, m), 9.80 (1H, s).

EXAMPLE 99 2-[(4-(1-cyclohexyltetrazol-5-yl)butyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR104##

¹ HNMR(CDCl₃) δ: 1.24-2.20 (14H, m), 2.87 (2H, m), 3.24-3.40 (2H, m), 4.10 (1H, m), 7.55 (1H, dd), 8.32 (1H, dd), 8.70 (1H, dd).

EXAMPLE 100 2[(4-(1-methyltetrazol-5-yl)butyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR105##

¹ HNMR(CDCl₃) δ: 1.80-2.22 (4H, m), 2.89 (1H, t)×2, 3.24-3.41 (2H, m), 4.00 (3H, s), 7.55 (1H, dd), 8.32 (1H, dd), 8.70 (1H, dd).

EXAMPLE 101 2-[(isobutoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR106##

¹ HNMR(CDCl₃) δ: 0.90 (6H, t), 1.93 (1H, m₇), 4.00 (2H, m₇), 4.16 (1H, d), 4.27 (1H, d), 7.55 (1H, dd), 8.32 (1H, d), 8.71 (1H, d).

EI (m/z): 299 (M+1)⁺.

EXAMPLE 102 2-[(n-butylaminocarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR107##

¹ HNMR(CDCl₃) δ: 0.87 (3H, t), 1.26-1.32 (2H, m₁₂), 1.46 (2H, m₅), 3.25 (2H, m₅), 3.89 (1H, d), 4.12 (1H, d), 6.81 (1H, s), 7.55 (1H, dd), 8.34 (1H, d), 8.69 (1H, d).

EI (m/z): 297 (M⁺).

EXAMPLE 103 2-methylsulfinylthiazolo[5,4-b]pyridine ##STR108##

¹ HNMR(CDCl₃) δ: 3.11 (3H, s), 7.54 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 198 (M⁺).

EXAMPLE 104 2-[(ethoxycarbonylmethyl)sulfinyl]thiazolo[4,5-b]pyridine ##STR109##

¹ HNMR(CDCl₃) δ: 1.27 (3H, t), 4.16 (1H, d), 4.28 (2H, q), 4.34 (1H, d), 7.48 (1H, dd), 8.42 (1H, dd), 8.85 (1H, dd).

EXAMPLE 105 2-[(ethoxycarbonylmethyl)sulfinyl]thiazolo[4,5-b]pyrazine ##STR110##

¹ HNMR(CDCl₃) δ: 1.27 (3H, t), 4.19 (1H, d), 4.28 (2H, q), 4.35 (1H, d), 8.69 (1H, d), 8.81 (1H, d).

EXAMPLE 106 2-[(ethoxycarbonylmethyl)sulfinyl)methyl]thiazolo[5,4-b]pyridine ##STR111##

¹ HNMR(CDCl₃) δ: 1.32 (3H, t), 3.77 (1H, d), 4.03 (1H, d), 4.28 (2H, q), 4.60 (1H, d), 4.77 (1H, d), 7.47 (1H, dd), 8.30 (1H, dd), 8.63 (1H, dd).

EXAMPLE 107 2-[(3-ethoxycarbonyl-2-propenyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR112##

¹ HNMR(CDCl₃) δ: 1.26 (3H, t), 4.01 (1H, ddd), 4.17 (2H, q, including 1H, unresolved), 6.07 (1H, dt), 6.83 (1H, quint), 7.55 (1H, dd), 8.33 (1H, dd), 8.71 (1H, dd).

EXAMPLE 108 2-[{(ethoxycarbonyl)difluoromethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR113##

¹ HNMR(CDCl₃) δ: 1.34 (3H, t), 4.40 (2H, q), 7.46 (1H, dd), 7.98 (1H, dd), 8.33 (1H, dd).

EXAMPLE 109 2-[(2-hydroxyethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR114##

¹ HNMR(CDCl₃) δ: 3.57-3.77 (2H, m), 4.89 (1H, m), 5.07 (1H, m), 7.31 (1H, ddd), 7.88 (1H, ddd), 8.37 (1H, ddd).

EXAMPLE 110 2[(2-acetoxyethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR115##

¹ HNMR(CDCl₃) δ: 1.89 (3H, s), 3.50 (1H, ddd), 3.60 (1H, ddd), 4.58 (1H, ddd), 4.63 (1H, ddd), 7.54 (1H, dd), 8.32 (1H, dd), 8.70 (1H, dd).

EXAMPLE 111 2-[(2-(1,3-dioxo-isoindol-2-yl)ethyl)sulfinyl]thiazolo[5,4-b]pyridine R1 ? ##STR116##

¹ HNMR(CDCl₃) δ: 3.67 (2H, m), 4.29 (2H, m), 7.48 (1H, dd), 7.70 (2H, dd), 7.81 (2H, dd), 8.21 (1H, dd), 8.64 (1H, dd).

EXAMPLE 112 2-[(isopentoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR117##

¹ HNMR(CDCl₃) δ: 0.90 (6H, m), 1.50 (1H, q), 1.63 (1H, m⁷), 4.15 (1H, d), 4.25 (2H, t), 7.56 (1H, dd), 8.33 (1H, d), 8.72 (1H, d).

EI (m/z): 313 (M+1)⁺.

EXAMPLE 113 2[(n-octyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR118##

¹ HNMR(CDCl₃) δ: 0.87 (3H, t), 1.22-1.36 (8H, m), 1.47 (2H, m), 1.74 (1H, m), 1.98 (1H, m), 3.23 (2H, m), 7.53 (1H, dd), 8.31 (1H, d), 8.68 (1H, d).

EI (m/z): 296 (M)⁺.

EXAMPLE 114 2-(isopentylsulfinyl)thiazolo[5,4-b]pyridine ##STR119##

¹ HNMR(CDCl₃) δ: 0.94 (6H, t), 1.58 (1H, m;), 1.73 (1H, m⁷), 1 88 (1H, m⁷), 3.15-3.32 (2H, m¹²), 7.53 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 355 (M+1)⁺.

EXAMPLE 115 2-[(n-octoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR120##

¹ HNMR(CDCl₃) δ: 0.88 (3H, t), 1.27-1.54 (10H, m), 1.60 (2H, m), 4.13 (1H, d), 4.19 (2H, t), 4.25 (1H, d), 7.55 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 355 (M+1)⁺.

EXAMPLE 116 2-[(cyclopentoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR121##

¹ HNMR(CDCl₃) δ: 1.54-1.73 (6H, m), 1.80-1.90 (2H, m), 4.11 (1H, d), 4.22 (1H, d), 7.55 (1H, dd), 8.32 (1H, d), 8.70 (1H, d).

EI (m/z): 310 (M)⁺.

EXAMPLE 117 2-[(N-cyclohexylcarbamoylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR122##

¹ HNMR(CDCl₃) δ: 1.21-1.90 (10H), 3.73 (1H, m), 3.86 (1H, d), 4.12 (1H, d), 6.73 (1H, d), 7.55 (1H, dd), 8.34 (1H, dd), 8.70 (1H, dd).

EI (m/z): 323 (M)⁺.

EXAMPLE 118 2[(N-methylcarbamoylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR123##

¹ HNMR(CDCl₃) δ: 2.64 (3H, d), 4.10 (1H, d), 4.22 (1H, d), 7.72 (1H, dd), 8.30 (1H, brs), 8.54 (1H, d), 8.75 (1H, brd).

EI (m/z): 255 (M)⁺.

EXAMPLE 119 2-[((1-cyclohexyltetrazol-5-yl)methyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR124##

¹ HNMR(CDCl₃) δ: 1.20-2.15 (10H), 4.57 (1H, m), 5.03 (1H, d), 5.50 (1H, d), 7.74 (1H, dd), 8.58 (1H, brd), 8.76 (1H, brd).

EI (m/z): 348 (M)⁺.

EXAMPLE 120 2[((1-methyltetrazol-5-yl)methyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR125##

¹ HNMR(CDCl₃ : DMSO-d₆ =5: 1): 4.18 (3H, s), 4.90 (1H, d), 5.30 (1H, d), 7.63 (1H, dd), 8.42 (1H, dd), 8.71 (1H, dd).

EI (m/z): 280 (M)⁺.

EXAMPLE 121 2-[(3-ethoxymethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR126##

¹ HNMR(CDCl₃) δ: 1.05 (3H, t), 3.37-3.44 (2H, m), 3.44-3.57 (2H, m), 3.88-4.00 (2H, m), 7.53 (1H, dd), 8.33 (1H, d), 8.69 (1H, d).

EI (m/z): 256 (M⁺).

EXAMPLE 122 6-chloro-2-[(2-ethoxymethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR127##

¹ HNMR(CDCl₃) δ: 1.04 (3H, t), 3.36-3.44 (1H, m), 3.44-3.57 (3H, m), 8.30 (1H, s), 8.62 (1H, s).

EI (m/z): 290 (M⁺).

EXAMPLE 123 2-[(2-ethoxymethyl)sulfinyl]thiazolo[4,5-c]pyridine ##STR128##

¹ HNMR(CDCl₃) δ: 1.04 (3H, t), 3.37-3.44 (1H, m), 3.48 (2H, q), 3.44-3.57 (1H, m), 3.90-4.02 (2H, m), 7.96 (1H, dd), 8.63 (1H, d), 9.38 (1H, s).

EI (m/z): 256 (M⁺).

EXAMPLE 124 2-(2-ethoxymethyl)sulfinyl]1H-imidazo[4,5-b]pyridine ##STR129##

¹ HNMR(CDCl₃) δ: 1.01 (3H, t), 3.46 (2H, q), 3.42-3.52 (1H, m), 3.93-4.04 (2H, m), 7.37 (1H, dd), 8.14 (1H, d), 8.75 (1H, d).

30 EI (m/z) 239 (M⁺).

EXAMPLE 125 2-[2(pyridin-2-yl)-ethylsulfinyl]thiazolo[4,5-b]pyridine ##STR130##

¹ HNMR(CDCl₃) δ: 3.22 (1H, m), 3.45 (1H, m), 3.68 (1H, m), 3.81 (1H, m), 7.12 (1H, m), 7.20 (1H, d), 7.51 (1H, m), 7.58 (1H, m), 8.30 (1H, m), 8.48 (1H, m), 8.67 (1H, d).

EI (m/z): 289 (M)⁺.

EXAMPLE 126 2[(2-oxazolidion-5-yl)methylsulfinyl]thiazolo[5,4-b]pyridine ##STR131##

¹ HNMR(CDCl₃) δ: 3.50 (1H, m), 3.63-3.91 (3H, m), 5.19-5.26 (1H, m), 7.66 (1H, m), 8.47 (1H, m), 8.70 (1H, m).

EI (m/z): 283 (M)⁺.

EXAMPLE 127 2[(3-methyl-2-butenyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR132##

¹ HNMR(CDCl₃) δ: 1.62 (3H, s), 1.78 (3H, s), 3.89 (1H, dd), 4.04 (1H, dd), 5.26 (1H, m), 7.54 (1H, dd), 8.33 (1H, d), 8.69 (1H, d).

EI (m/z): 252 (M)⁺.

EXAMPLE 128 2[(ethoxycarbonylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR133##

¹ HNMR(CDCl₃) δ: 1.26 (3H, t), 4.14 (1H, d), 4.24 (1H, d), 4.27 (2H, q), 7.55 (1H, dd), 8.32 (1H, d), 8.71 (1H, d).

EI (m/z): 270 (M)⁺.

EXAMPLE 129 2-[{2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR134##

Dissolved in 7 ml of acetic acid was 3.6 g of the compound obtained in Example 13, and 1.07 ml of a 35% hydrogen peroxide solution and 50 mg of sodium tungstenate were added to the solution. The solution was stirred for 8 hours while cooled with ice or water, and was then adjusted to pH 7 by the addition of an aqueous solution of sodium hydrogencarbonate and sodium hydrogencarbonate, and extracted with 300 ml of ethyl acetate. The resulting ethyl acetate phase was washed once with an aqueous solution of sodium thiosulfate and once with a brine solution, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel column chromatography, and eluting with n-hexane-ethyl acetate (1:1 to 1:2) to obtain the title compound (2 g).

¹ HNMR(CDCl₃) δ: 1.02 (12H), 1.36-1.40 (4H, m), 1.48-1.53 (1H, m), 1.62 (1H, m), 2.81-2.89 (1H, m), 3.16-3.26 (1H, m), 3.28-3.34 (2H, m), 7.52 (1H, dd), 8.30 (1H, d), 8.68 (1H, d).

The compounds having the general formula (I) wherein n=1 were synthesized in the same manner as in Example 129. The compound having the general formula (I) wherein n=2 were synthesized in similar manners as in Example 129 except that 1.5 to 2.0 equivalents of a 35% hydrogen peroxide solution was used. The compounds obtained are shown in Examples 130-152.

EXAMPLE 130 2-[(2-di-isopropylaminomethyl)sulfinyl]thiazolo[4,5-c]pyridine ##STR135##

¹ HNMR(CDCl₃) δ: 1.03 (6H, d), 1.10 (6H, d), 2.92-3.00 (1H, m), 3.11 (2H, m), 3.14-3.23 (2H, m), 3.36-3.44 (1H, m), 7.96 (1H, d), 8.62 (1H, d), 9.36 (1H, s).

EXAMPLE 131 2-[(2-di-isopropylamino)methyl]sulfinyl6-trifluoromethylthiazolo[4,5-b]pyridine ##STR136##

¹ HNMR(CDCl₃) δ: 1.03 (3H, s), 1.04 (3H, s), 1.10 (3H, s), 1.11 (3H, s), 3.01 (1H, m), 3.05-3.25 (4H, m), 3.50 (1H, m), 8.68 (1H, s), 9.05 (1H, s).

EXAMPLE 132 2-[2-(1-methylpyrrolidin-2-yl)ethylfulfinyl]thiazolo[4,5-c]pyridine ##STR137##

¹ HNMR(CDCl₃) δ: 1.5-1.8 (5H), 1.96-2.24 (3H), 2.27 and 2.30 (3H, s), 2.98-3.43 (3H, m), 7.96 (1H, dd), 8.63 (1H, d), 9.38 (1H, s).

EXAMPLE 133 2-[{2-(2,2,6,6-tetramethylpiperidin-1-yl)methyl}sulfinyl]-6-trifluoromethylthiazolo[4,5-b]pyridine ##STR138##

¹ HNMR(CDCl₃) δ: 1.02 (6H, s), 1.03 (6H, s), 2.40 (4H, m), 2.51 (2H, m), 2.84 (1H, m), 3.24 (1H, m), 3.35 (1H, m), 3.42 (1H, m), 8.70 (1H, d), 9.08 (1H, d).

EXAMPLE 134 2-[{2-2,2,6,6-tetramethylpiperidin-1-yl)methyl]sulfinyl]sulfinyl]1H-imidazo[4,5-b]pyridine ##STR139##

¹ HNMR(CDCl₃) δ: 1.00 (12H, d), 1.34-1.39 (4H, m₃), 1.47-1.50 (2H, m₃), 2.80-2.88 (1H, m), 3.19-3.27 (1H, m), 3.31-3.40 (2H, m), 7.37 (1H, dd), 8.14 (1H, d), 8.74 (1H, d).

EI (m/z): 334 (M⁺), 335 (M⁺ 1)

EXAMPLE 135 2[(carbamoylmethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR140##

¹ HNMR(CDCl₃) δ: 4.15 (2H, ABq), 7.53 (1H, brs), 7.70 (1H, dd), 7.80 (1H, brs), 8.52 (1H, dd), 8.74 (1H, dd).

EXAMPLE 136 2[(2-di-isopropylaminomethyl)sulfinyl]thiazolo[4,5-b]pyridine ##STR141##

¹ HNMR(CDCl₃) δ: 1.03 (6H, d), 1.10 (6H, d), 2.98 (1H, m), 3.01-3.30 (4H, m), 3.51 (1H, m), 7.43 (1H, dd), 8.39 (1H, dd), 8.81 (1H, dd).

EXAMPLE 137 2-[(2-di-isopropylaminomethyl)sulfinyl)methyl]thiazolo[5,4-b]pyridine ##STR142##

¹ HNMR(CDCl₃) δ: 1.01 (6H, d), 1.04 (6H, d), 2.75-3.10 (6H, m), 4.41 (1H, d), 4.60 (1H, d), 7.46 (1H, dd).

EXAMPLE 138 2-[(2-morpholinomethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR143##

¹ HNMR(CDCl₃) δ: 2.47 (4H, t), 2.84-3.00 (1H, m), 3.32-3.54 (3H, m), 7.54 (1H, dd), 8.28 (1H, d), 8.67 (1H, d).

EI (m/z) 297 (M⁺).

EXAMPLE 139 2-[(2-morpholinomethyl)sulfonyl]thiazolo[5,4-b]pyridine ##STR144##

¹ HNMR(CDCl₃) δ: 2.35 (4H, s), 2.93 (2H, t), 3.17 (4H, s), 3.74 (2H, t), 7.61 (1H, dd), 8.45 (1H, dd), 8.80 (1H, d).

EI (m/z): 313 (M⁺).

EXAMPLE 140 2-[(2-morpholinomethyl)sulfinyl]thiazolo[4,5-c]pyridine ##STR145##

¹ HNMR(CDCl₃) δ: 2.46 (4H, t), 2.86-3.00 (2H, m), 3.37-3.43 (6H, m), 7.98 (1H, d), 8.64 (1H, d), 9.34 (1H, s).

EI (m/z): 297 (M⁺).

EXAMPLE 141 2[(2-N,N-diethylaminomethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR146##

¹ HNMR(CDCl₃) δ: 1.00 (6H, t), 2.52-2.66 (4H, m), 2.87-2.94 (1H, m), 3.08-3.16 (1H, m), 3.24-3.33 (1H, m), 3.37-3.44 (1H, m), 7.52 (1H, dd), 8.28 (1H, d), 8.66 (1H, d).

EI (m/z): 283 (M⁺).

EXAMPLE 142 6-chloro-2-[(2-morpholinomethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR147##

¹ HNMR(CDCl₃) δ: 2.46 (4H, t), 2.84-3.00 (2H, m), 3.32-3.44 (4H, m), 3.46-3.52 (2H, m), 8.26 (1H, d), 8.26 (1H, d), 8.64 (1H, d).

EI (m/z): 331 (M⁺).

EXAMPLE 143 2-[(2-morpholinoethyl)sulfinyl]imidazo[4,5-b]pyridine ##STR148##

¹ HNMR(CDCl₃) δ: 2.43 (4H, t), 2.92 (1H, m), 3.37 (2H, m), 3.43-3.55 (4H, m), 7.38 (1H, dd), 8.13 (1H, d), 8.76 (1H, d).

EI (m/z): 280 (M⁺)

EXAMPLE 144 2-[(2-(1-methylpyrrolidin-2-yl)ethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR149##

¹ HNMR(CDCl₃) δ: 1.42-1.55 (1H, m), 1.61-1.77 (3H, m), 1.88-1.98 (1H, m), 1.98-2.07 (1H, m), 2.19 (1H, q), 2.30 (3H, d), 3.03-3.07 (1H, m), 3.13-3.21 (1H, m), 3.25-3.29 (1H, m), 3.32-3.41 (1H, m), 7.53 (1H, m), 8.31 (1H, d), 8.69 (1H, d).

EI (m/z): 295 (M⁺).

EXAMPLE 145 2-[(2-(1-methylpyrrolidin-2-yl)ethyl)sulfonyl]thiazolo[5,4-b]pyridine ##STR150##

¹ HNMR(CDCl₃) δ: 1.47 (1H, m), 1.72 (2H, m), 1.94 (2H, m), 2.16 (2H, m), 2.27 (3H, s), 2.30-2.36 (1H, m), 3.03 (1H, m), 3.47 (1H, m), 3.68 (1H, m), 7.62 (1H, dd), 8.47 (1H, d), 8.79 (1H, d).

EI (m/z): 311 (M⁺).

EXAMPLE 146 2-[(2-ureidoethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR151##

¹ HNMR(CDCl₃) δ: 3.40-3.50 (4H, m), 7.72 (1H, dd), 8.52 (1H, d), 8.52 (1H, d), 8.73 (1H, d).

EI (m/z): 302 (M⁺).

EXAMPLE 147 2-[(1-methylpiperidin-3-yl)methylsulfinyl]thiazolo[5,4-b]pyridine ##STR152##

¹ HNMR(CDCl₃) δ: 1.16-1.33 (1H, m), 1.58-1.61 (2H, m), 1.75 (2H, m), 1.83-1.93 (2H, m), 2.25 (3H, d), 2.36-2.48 (1H, m), 2.65 (1H, m), 2.93-2.83 (1H, dd), 3.12-3.19 (2H, m), 7.53 (1H, dd), 8.32 (1H, d), 8.68 (1H, d).

EI (m/z): 295 (M⁺).

EXAMPLE 148 2-[(1-methylpiperidin-4-yl)sulfinyl]thiazolo[5,4-b]pyridine ##STR153##

¹ HNMR(CDCl₃) δ: 1.84-2.15 (6H, m), 2.27 (3H, d), 2.95-2.98 (2H, m), 3.07-3.13 (1H, m), 7.53 (1H, dd), 8.33 (1H, d), 8.68 (1H, d).

EI (m/z): 281 (M⁺).

EXAMPLE 149 2-[(2-di-isopropylaminoethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR154##

¹ HNMR(CDCl₃) δ: 1.03 (6H, d), 1.08 (6H, d), 2.93-2.98 (1H, m), 3.04-3.14 (2H, m), 3.16-3.23 (2H, m), 3.32-3.40 (1H, m), 7.52 (1H, dd), 8.28 (1H, d), 8.67 (1H, d).

EI (m/z): 311 (M⁺).

EXAMPLE 150 2-[(2-di-isopropylaminoethyl)sulfonyl]thiazolo5,4-b]pyridine ##STR155##

¹ HNMR(CDCl₃) δ: 0.95 (12H, t), 2.96 (2H, m), 3.07 (2H, t), 3.63 (2H, t), 7.62 (1H, dd), 8.47 (1H, d), 8.79 (1H, d).

EI (m/z) 327 (M⁺).

EXAMPLE 151 2[(3-(1-methylpiperazin-4-yl)propyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR156##

¹ HNMR(CDCl₃) δ: 1.80-1.91 (1H, m), 2.12-2.23 (1H, m), 2.28 (3H, s), 2.39-2.56 (9H, m), 3.30 (3H, m), 7.53 (1H, dd), 8.31 (1H, d), 8.68 (1H, d).

EI (m/z): 324 (M⁺).

EXAMPLE 152 2-[(2-di-n-butylaminoethyl)sulfinyl]thiazolo[5,4-b]pyridine ##STR157##

¹ HNMR(CDCl₃) δ: 0.89 (6H, t), 1.27-1.35 (4H, m), 1.35-1.43 (4H, m), 2.43-2.50 (4H, m), 2.85-2.91 (1H, m), 3.11-3.18 (1H, m), 3.24-3.27 (1H, m), 3.38-3.45 (1H, m), 7.52 (1H, dd), 8.30 (1H, d), 8.67 (1H, d).

EI (m/z): 339 (M⁺).

EXAMPLE 153 Sodium (thiazolo[5,4-b]pyridin-2-yl)sulfinylacetate ##STR158##

In ethanol, the compound set forth in Ex. 93 was hydrolyzed with 1N sodium hydroxide, and was purified by column chromatography (LH-20, Pharmacia Inc.) to obtain the title compound.

¹ HNMR(CDCl₃) δ: 4.03 (2H, d), 7.50 (1H, dd), 8.10 (1H, d), 8.41 (1H, d).

EXAMPLE 154 Pharmaceutical Composition

    ______________________________________                                                           mg/tablet                                                    ______________________________________                                         (a)    Oral tablet                                                                    Compound of Example 79                                                                          15                                                            Lactose            49.2                                                        Starch           30                                                            Polyvinylpyrrolidone                                                                             6                                                            Microcrystalline Cellulose                                                                      18                                                            Colloidal Silica   1.2                                                         Magnesium Stearate                                                                                0.6                                                         Total            120                                                    (b)    Oral Capsule                                                                   Compound of Example 79                                                                          25                                                            Lactose          100                                                           Starch           13                                                            TC-5             10                                                            Magnesium Stearate                                                                               2                                                            Total            150                                                    ______________________________________                                    

EXAMPLE 155 Pharmacological Data

1. Water-immersion, restraint stress ulceroqenic testing

Wister male rats (11-week age) fasted for 18 hours were placed in a restraint cage, which was in turn immersed to a depth of the pectoral region in water at 20° to 22° C. to leave the rats under stress for six hours. Then, the rats were drawn up from the water and put down by vertebral dislocation. Afterwards, the stomach was removed, infused with 50 ml of a 5% aqueous solution of formalin and was wholly immersed in the same solution for 30 minutes for fixation. The fixed sample was dissected along the curvatura ventriculi major, and the ulcerated regions were measured along their major length (in mm) by means of slide calipers. The total sum of the measurements per rat is a value of ulceration. The compounds under test, suspended i n 0. 5% carboxymethylcellulose (CMC), were administered to the rats at a single dose of 5 ml/kg body weight (corresponding to 30 mg/kg body weight of the compound) one hour prior to the stressing. To a control group, only 0.5% CMC was administrated at a dose of 5 ml/kg weight. The rate of depression of ulceration was calculated according to the following equation: ##EQU1##

The results are set forth in Table 1.

2. Ethanol-induced ulceration

Five (5) ml/kg of 100% ethanol was orally administrated to Donryu masculine rats fasted for 48 hours and dehydrated for 24 hours. One hour later, the rats were put down in similar manners as mentioned above test to remove and treat the stomach. The compounds under test, suspended in 0.5% CMC, were orally administered to the rats at a dose of 5 ml/kg body weight (corresponding to 30 mg/kg body weight of that compound) one hour prior to the administration of ethanol. A control group, to which only 0.5% CMC was administered, showed a nearly 100% erosion, whereas the compound of Example 79, for instance, achieved a 98% depression of erosion. Effects of other compounds under test upon ulceration, determined in similar manners as mentioned above, are set forth in Table 2.

3. Toxicity

The compounds of the present invention are of low toxicity, as appreciated from Example compound Nos. 79, 104 and 133 having up to 1 g/kg of LD₅₀ value (mice, by an oral).

                  TABLE 1                                                          ______________________________________                                         Compound of    % Ulceration                                                    Example No.    Inhibition                                                      ______________________________________                                          47            99                                                               48            99                                                               51            88                                                               65            58                                                               70            42                                                               79            76                                                               84            75                                                               89            72                                                               93            73                                                              100            95                                                              101            75                                                              103            84                                                              104            68                                                              110            79                                                              117            77                                                              120            86                                                              121            67                                                              122            13                                                              123            15                                                              124            25                                                              125            44                                                              126            60                                                              127             0                                                              128            91                                                              129            99                                                              130            76                                                              131            71                                                              133            98                                                              135            86                                                              136            94                                                              138            68                                                              139            47                                                              140            58                                                              141            41                                                              142            13                                                              143            54                                                              144            85                                                              145            68                                                              146            19                                                              147            64                                                              148            78                                                              149            99                                                              150            61                                                              151            39                                                              ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                         Compound of    % Ulceration                                                    Example No.    Inhibition                                                      ______________________________________                                          79            98                                                              128            99                                                              138            97                                                              149            94                                                              ______________________________________                                     

What is claimed is:
 1. A compound having the formula (I): ##STR159## in which A and D, which are different from each other, represent --CH═or --N═;X represents --NH-- or --O--; Y represents --(CH₂)_(p) wherein p is an integer form 1 to 4; R¹ represents a hydrogen atom, a C₁₋₄ alkyl group which may be optionally substituted, a halogen atom or a C₁₋₄ alkoxy group which may be optionally substituted; R² represents --NR³ R⁴ wherein R³ and R⁴ which may be the same or different, represent a hydrogen atom or a C₁₋₆ alkyl group or --NR³ R⁴ forms a saturated heterocyclic ring which has five or six rings members, and which may optionally contain in the ring one oxygen atom and may optionally be substituted, and n represents an integer from 0 to 2, or a pharmaceutically acceptable salt thereof.
 2. A compound as claimed in claim 1 selected from 2-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethylthio]oxazolo [4,5-b]pyridine; and 2-[2-(2,2,6,6-tetramethylpiperidine-1-yl)ethylthio]oxazolo [5,4-b]pyridine.
 3. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier therefor.
 4. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 2 and a pharmaceutically acceptable carrier therefor. 